Methotrexate-Related Pulmonary Complications in Rheumatoid Arthritis

434 Annals of the Rheumatic Diseases 1994; 53: 434-439

REVIEW Ann Rheum Dis: first published as 10.1136/ard.53.7.434 on 1 July 1994. Downloaded from Methotrexate-related pulmonary complications in rheumatoid arthritis

Pilar Barrera, Roland F J M Laan, Piet L C M van Riel, P N Richard Dekhuijzen, Agnes M Th Boerbooms, Levinus B A van de Putte

Methotrexate (MTX) was described as a drug cosis,2627 aspergillosis,28 29 disseminated histo- in 1946' and first used in the treatment of plasmosis,28 parainfluenza virus infection'2 and human disease (childhood leukaemia) in cytomegalovirus pneumonia.30 Pulmonary 1948.2 Successful MTX treatment for candidiasis was described in one patient with rheumatoid arthritis (RA) and psoriasis was polymyositis/dermatomyositis treated with reported in 1951,3 although the interest in this MTX3' but, to our knowledge, not in RA. drug at that time was probably overshadowed Although some of the reported infections by the impressive results of cortico-steroid appeared during concomitant treatment with treatment until approximately 1980. MTX was corticosteroids, these studies suggest a approved by the food and drug administration potential immunosuppressive effect of low- (FDA) for the treatment of severe and dis- dose MTX treatment at least in some patients. abling psoriasis in 1971 and for RA only in The present review will focus on MTX- 1988.4 pneumonitis. MTX-related pulmonary toxicity was first observed during treatment of childhood leukaemia in 19695 and later in malig- Pathogenesis nancies, psoriasis6 7 and polymyositis.7 I The mechanism of MTX-induced lung Though it was postulated that pulmonary pathology remains unclear. Lung damage due toxicity would appear only with a weekly dose to folate deficiency has been suggested32 but higher than 20 mg,7 this did not prove to be seems unlikely since MTX pneumonitis may true when in 1983 pneumonitis was also occur after a single MTX dose33" and is not reported during low-dose MTX treatment for prevented by folinic acid treatment.35 A hyper-

RA9 10 sensitivity reaction is suggested by findings in http://ard.bmj.com/ lung biopsies: interstitial pneumonitis, granuloma formation and bronchiolitis,7 and in Infectious and non infectious pulmonary brochoalveolar lavage: lymphocytic alveolitis, complications increased eosinophils and reversed CD4/CD8 In recent years there has been an increase in ratio,3637 together with the clinical findings of the number of reports of pulmonary fever, peripheral eosinophilia and response to

complications associated with low-dose corticosteroids. The reports of spontaneous on September 30, 2021 by guest. Protected copyright. methotrexate therapy for rheumatic and non- remission during MTX treatment7 and rheumatic diseases including both non rechallenge of the drug without recurrence of infectious and infectious pathology. Among lung pathology'3 argue more for an the non infectious complications observed in idiosyncratic reaction than for hypersensitivity. patients with RA, interstitial pneumonitis has A specific cellular immune reaction to the drug been most often reported7 9-13 (more than 35 has been suggested by the production of a cases since the first reports in 1983).9 "0 lymphokine which inhibits leukocyte migration Interstitial lung fibrosis has been observed [leukocyte inhibitor factor (LIF)] by peripheral during MTX treatment for RA, malignancies blood lymphocytes after incubation with and psoriasis.6 1' Furthermore, one case of MTX. LIF production was observed in accelerated pulmonary nodulosis'4 and one of patients with MTX pneumonitis but not in drug-induced asthma'5 have so far been other patients treated with MTX or healthy Departments of Rheumatology and described during MTX treatment for RA. controls.38 39A toxic drug reaction is suggested Pulmonology*, Lung fibrosis and nodulosis may be pulmonary by the accumulation of MTX in lung tissue,40 University Hospital manifestations of RA,16 and it is therefore the biopsy findings of alveolar and non-specific Nijmegen, The to and the resolution of Netherlands difficult to ascribe this pathology only MTX lung injury,6 pathology P Barrera treatment. Two other complications, so far after stopping or lowering the drug.4' The fact RFJMLaan only observed during treatment with MTX in that pulmonary pathology does not appear to P LC M van Riel are oedema'7'18 be related to cumulative MTX dose argues, P N R Dekhuijen* malignant diseases, pulmonary A M Th Boerbooms and isolated pleuritis.'9 against this hypothesis. L B A van de Putte Among the pulmonary infections during Correspondence to: MTX treatment of RA, the most frequently Dr Pilar Barrera, Department of reported has been Pneumocystis cannii pneu- Risk factors Rheumatology, University monia with more than eight cases published Age, sex, and disease duration are not Hospital Nijmegen, PO Box of MTX- 9101, 6500HB Nijmegen, since 1983.2"25 Less frequently observed associated with the development The Netherlands. infections include pulmonary cryptococ- pneumonitis. This complication has been Methotrexate-related pulmonaty complications in rheumatoid arthritis 435

observed after oral,4' intravenous,42 intra- character of the diagnosis. The incidence of muscular,41 intrathecal43 and even local34 abnormalities in clinical, laboratory and administration of MTX. No correlation has radiological examination in patients with Ann Rheum Dis: first published as 10.1136/ard.53.7.434 on 1 July 1994. Downloaded from been found between the occurrence of lung MTX-pneumonitis is difficult to estimate since toxicity and cumulative or weekly dose or this complication is relatively uncommon and dosage schedule.'3 Pneumonitis has been large patient series are lacking. Data presented observed after as little as 12X5 mg MTX33 34 in the following sections were deducted from and may appear even weeks after dis- previous studies. continuation of treatment.446 In view of the relative rarity of MTX pneumonitis in other non-malignant diseases like psoriasis47 and Clinical features and physical bronchial asthma,48 a propensity to pulmonary examination involvement in RA has been suggested33 but so The most usual complaints include dyspnoea far comparative studies on the incidence of and fever.9-l3 Non productive cough has been MTX-pneumonitis in RA and other diseases reported in 75% of the patients.54 Pleuritic are lacking. A possible relationship between chest pain may also be present but is rare.3 19 certain HLA haplotypes and increased risk for In most patients a subacute clinical course is MTX-pneumonitis has been mentioned in two observed during some weeks, but acute previous reports: DRw3 in one case33 and presentations have been also described.33 On A2,24;DR4 in two cases.49 We also observed examination, tachypnoea (in 38-52% of the the HIA DR4 haplotype in four offive patients patients), crepitant rales (in 31-45% of the with MTX-related lung toxicity admitted to patients) and cyanosis (in 52% of the patients) our unit during 1993, but studies in larger are common findings.7 913 5 Abnormalities on patient groups are needed. auscultation may be disproportionately scarce Renal function impairment'3 50 and con- compared with the extensive radiological comitant use of non steroidal anti-inflam- findings.33 matory drugs'2 have been suggested to predispose to MTX-toxicity in some studies but this has not been confirmed by others.5' Laboratory investigations Specific risk factors for the development of As for the clinical findings and physical MTX pneumonitis are not known exactly but examination, no specific results of laboratory some studies have suggested that a history tests are diagnostic for MTX-pneumonitis. of smoking,'2 pre-existing pulmonary Hypoxaemia is observed in 90-95% of the disease2 52 53 and abnormal chest radiographs cases.7 9-13 54 The white blood cell count may before MTX institution53 might be predis- be normal7 or show moderate leukocytosis posing factors. without left shift.9 13 Mild eosinophilia has

been reported in 41% of the patients7 54 and http://ard.bmj.com/ elevated levels of lactate dehydrogenase Diagnosis (LDH)'0 13 have been reported. The diagnosis of MTX-pneumonitis is difficult Investigations directed to exclude infectious since there are no pathognomonic findings and pathology should consist of extensive cultures this condition may mimic other pulmonary of sputum, blood and bronchoalveolar lavage diseases. When a patient treated with MTX (BAL) fluid and serological test for common

develops new respiratory symptoms, the respiratory viruses, mycoplasma, rickettsia and on September 30, 2021 by guest. Protected copyright. differential diagnosis includes MTX- legionella. Microscopical examination of BAL pneumonitis, rheumatoid lung disease, and fluid is recommended to exclude Pneumocystis pulmonary infection or emboli. Exclusion of carinii, fungi and mycobacteria. BAL cell other pathology, particularly of infectious analysis usually reveals* hypercellularity and origin, is time consuming and therefore MTX- lymphocytosis.3637 Mild eosinophilia36 or pneumonitis is often diagnosed retrospectively. neutrophilia37 and increased percentages of Criteria, proposed by two different groups,'2 13 either CD436 or CD8 lymphocytes37 38 have (table 1) are helpful for diagnostic purposes, also been reported. The diagnostic value of but the term 'definite' MTX-pneumonitis'2 BAL cell analysis is limited since lympho- should be avoided in view of the presumptive cytosis, increases in CD4 and decreases in

Table 1 Diagnostic criteria ofMTX-pneumonitis Searles et al 198712 Carson et al 1987'3 Clinical 1 Acute onset of dyspnoea 1 Course consistent with a hypersensitivity reaction 2 Fever > 38'C 3 Tachypnoea 2 28/min and nonproductive cough Laboratory 4 WBC c 15,000 X 109A/ (± eosinophilia) 2 Exclusion of infection and other pulmonary disease 5 P02 on room air < 55 mm/Hg at admission 6 Negative blood and sputum cultures (obligatory) Radiological 7 Pulmonary interstitial or alveolar infiltrates 3 Infiltrates Pulmonary function tests 8 Restrictive pattern, decreased diffusion Histopathology 9 Bronchiolitis/interstitial pneumonitis with giant cells 4 Consistent with drug-induced injury without evidence ofpathogenic micro-organisms Classification Definite 6 out of 9 criteria not used Probable 5 out of 9 criteria 2 3 out of 4 criteria Possible 4 out of 9 criteria 2 out of 4 criteria 436 Barrera, Laan, van Riel, Dekhuijzen, Boerbooms, van de Putte

CD8 lymphocytes may be present in patients described but this may be observed also in with RA (not treated with MTX) even in the uncomplicated RA.9 13 Electron microscopy absence of rheumatoid lung disease.55 examination reveals intact basement mem- Ann Rheum Dis: first published as 10.1136/ard.53.7.434 on 1 July 1994. Downloaded from Furthermore, similar findings and increased branes and proliferation and desquamation of percentage of eosinophils have been observed lymphocytes and eosinophils.7 during hypersensitivity pneumonitis induced by other antirheumatic drugs like gold, D-penicillamine, non-steroidal anti-inflam- Treatment and outcome matory drugs and more rarely azathioprine and The therapy for MTX-pneumonitis has not sulphasalazine.'6 55 been analysed in controlled trials and experience is based on case reports. Besides supportive therapy, withdrawal of MTX seems Radiological and scintigraphic a logical approach though resolution of examinations pulmonary pathology despite continuation of A great variety ofchest x ray patterns have been MTX treatment has been reported.5 41 described but bilateral interstitial (in 50% of Reinstitution of MTX treatment after MTX- the patients) or mixed interstitial and alveolar related lung toxicity has been reported in five infiltrates (in 41% of the patients), most cases without event7 12 13 70 but recurrence of prominent at the lung basis are probably the pulmonary complications may occur.13 71 most common.9 13 54 Unilateral infiltrates,'3 57 a Though improvement without corticosteroids reticulonodular pattern58 and more rarely has been reported,'3 41 58 this therapy might pleural effusions'9 and transient hilar hasten recovery9 10 13 57 and is recommended in lymphadenopathy7 57 have also been reported. high dose until clinical improvement is evident. High-resolution computer tomography may No worsening of MTX-pneumonitis has yet show parenchymal ground-glass opacities been observed when the dose of steroids is (alveolitis), granulomas and fibrosis.59-61 tapered. There is no evidence that Gallium-6762 63 and Tc-99 diethylene- corticosteroids or folinic acid prevent MTX- triamine-pentacetate (DTPA) lung scinti- related pulmonary disease.35 Effective treat- graphy64 may show increased pulmonary ment with daunorubicine in three leukaemia uptake. These are sensitive but non-specific patients with MTX-pneumonitis has been investigations in drug-induced lung disease reported72 but, for evident reasons, this drug and their value in the diagnosis and follow up has not been used in non malignant diseases. of lung pathology related to MTX or other In some cases (that is, when lung biopsy is not drugs has yet to be determined. performed), additional antibiotic treatment may be warranted in view of the difficult exclusion of some pulmonary infections. tests Empirical treatment for Pneumocystis carinii Pulmonary function http://ard.bmj.com/ Apart from hypoxaemia, thorough pulmonary should be considered in such patients. The function evaluation during MTX-pneumonitis outcome of MTX-pneumonitis is usually has not often been reported. Restrictive and favourable with clinical amelioration usually obstructive patterns and low CO diffussion preceeding radiological and functional capacity7 52 have been observed. So far improvement.7 12 57 However, fatal outcome uncomplicated long term treatment with low has been described in both rheumatic7 57 58 and dose MTX has not been associated with non-rheumatic7 18 diseases. deterioration in pulmonary function.65-67 on September 30, 2021 by guest. Protected copyright. Prevalence in the literature and review of Lung biopsy own experience This procedure has been recommended not Data about the prevalence of MTX- only for histopathological examination but also pneumonitis in RA show a great variation. to exclude other diseases, especially infections. While in some large studies73 74 such pathology Before performing a lung biopsy, the clinician was not observed at all, several retrospective should balance the condition of the individual and prospective studies have reported patient against the morbidity and mortality68 prevalence rates between 0 3 and 11 6% associated with such a procedure. In some (table 2). 1113 49 75-83 The incidence of MTX studies, patients have been managed without pneumonitis is not mentioned in most studies. pathological examination of lung tissue. 13 Carson et al 13 observed 3 9 cases per 100 Transbronchial biopsy may be adequate in patient years of MTX therapy in a establishing the diagnosis,57 but ifinconclusive, retrospective study including 163 patients. The open lung biopsy may be required.'0 13 69 The prospective ARAMIS programme reported pathological findings of interstitial pneu- incidence rates of dyspnoea and wheezing of monitis with lymphocytic9 10 13 57 and some- respectively six and two per 1000 patient years times eosinophilic4' 57 infiltration, bronchiolitis among 497 patients treated with MTX, the and granuloma formation9 10 57 resemble other incidence of MTh pneumonitis was not forms ofhypersensitivity pneumonitis and have mentioned in this study.84 In our centre, low- lead to the classification of MTX-pneumonitis dose MTX treatment for RA, systemic as a hypersensitivity reaction. Alveolar damage sclerosis (SS) and ankylosing apondylitis (AS) with hyaline membranes and type 2 alveolar has been used since 1984, 1988, and 1992, cell hyperplasia and dysplasia57 may also be respectively. Up to this year, sporadic cases of present. Interstitial fibrosis7 9 10 13 has been MTX-related pulmonary toxicity (see below) Methotrexate-related pulmonary complications in rheumatoid arthritis 437

Table 2 Prevalence ofMTXpneumonitis in the literature a pathogenic micro-organism. To achieve this Author Publication Study design Observation Number cases! Prevalence Reference goal, transbronchial or open lung biopsy have year years Total number been Ann Rheum Dis: first published as 10.1136/ard.53.7.434 on 1 July 1994. Downloaded from patients recommended, but the risks inherent to these procedures should be taken into account, Sostman 1976 retrospective 7 7/92 7-6% 7 especially in patients with a poor St Clair 1985 retrospective not mentioned 3/95 3-1% 57 pulmonary Cannon 1986 retrospective not mentioned 5/127 3-9% 75 condition. Our approach to a patient with Carson 1987 retrospective 8 9/163 5-5% 13 MTX-related Gispen 1987 retrospective 3 1/72 144% 58 suspected lung pathology Searles 1987 retrospective 8 4/73 5-5% 12 consists of: MTX discontinuation, supportive Alarcon 1989 retrospective 5 2/152 133% 76 therapy, comprehensive diagnostic Scully 1991 retrospective 5 11/124 8-8% 77 procedures Hargreaves 1992 retrospective 3 5/43 11-6% 11 to exclude infection (including BAL analysis), Buchbinder 1993 retrospective 5 2/587 0 3% 78 empirical antimicrobial treatment and, in some Boh 1986 prospective 2 3/59 5-/1% 79 Andersen 1987 prospective not mentioned 1/40 2-5% 80 cases, intravenous corticosteroids until clinical Haranhan 1989 prospective 4 1/128 0-8% 81 and radiological improvement appears. This Drosos 1990 prospective 2 1/137 077% 82 Kremer 1992 prospective 7-5 2/29 6-9% 49 approach is warranted as excluding infection is Weinblatt 1992 prospective 7 2/26 7-7% 83 difficult, time consuming and sometimes retrospective. Though no predisposing factors for the were observed. In contrast, in 1993 such development of MTX pneumonitis are known, pathology appeared in five patients within a abnormalities on chest radiographs and period of three months, and at least four of pulmonary pathology previous to MTX these cases satisfied the criteria of MTX treatment have been suggested to increase the pneumonitis. 12 13 Apart from this cluster of five risk of pulmonary toxicity. For this reason and cases, we performed a review among more than also to exclude underlying rheumatoid lung 220 patients29 71 85-90 enrolled in prospective disease, chest radiographs should be studies with low-dose MTX (table 3) and all performed before institution of MTX hospital admissions to our unit, from 1984 to treatment. Uneventful MTX-treatment is not 1993, where pulmonary pathology was associated with deterioration in pulmonary recorded. Eight additional cases of MTX- function, therefore in our practice, pre- related pulmonary pathology were identified treatment pulmonary function tests and blood consisting of four episodes of MTX- gas analysis are selectively performed in pneumonitis (two in the same patient7l) and patients with a history of lung pathology. four pulmonary infections. The latter Since MTX-related lung toxicity is encompassed two cases of viral pneumonitis potentially fatal, patients should be instructed (one of them during leukopenia87), one case of to report any new pulmonary symptoms pulmonary aspergillosis29 and one case of without delay. pneumococcal pneumonia during leukopenia. We thank F H J van den Hoogen, P J S M Kerstens, C J Including the five patients observed during Haagsma and M C W Creemers for their clinical studies. We http://ard.bmj.com/ 1993, we have therefore observed 13 cases of are also grateful to P Donnelly and J W M van der Meer for MTX-related pulmonary pathology in the past the revision of this manuscript. nine years.

1 Angier R B, Boothe J W, Hutchings B L. The structure and synthesis of the liver L. Casei factor. Science 1946; 103: 667-9. Conclusion 2 Farber S, Diamond L K, Mercer R D, Sylvester R F Jr, Solff J This review of the literature and our own A. Temporary remission in acutet leukemia in children on September 30, 2021 by guest. Protected copyright. shows produced by folic antagonist 4-aminopteroyl-glutamic experience that, though probably acid (aminopterin). N EnglJ_ Med 1948; 238: 787-93. uncommon, pulmonary pathology related to 3 Gubner R, August S, Ginsberg V. Therapeutic suppression of tissue reactivity II. Effect of aminopterin in rheumatoid low-dose MTX treatment for rheumatic arthritis and psoriasis. AmJMed Sci 1951; 221: 176-82. diseases has been well documented. 4 Tugwell P, Bennett K, Bell M, Gent M. Methotrexate in rheumatoid arthritis. Feedback on American College of There are no pathognomonic clinical, Physicians Guidelines. Ann Int Med 1989; 110: 581-3. laboratory or radiological features which allow 5 Acute Leukemia Group B. Acute lymphocytic leukemia in children. Maintenance therapy with methotrexate differentiation between infectious and non- administered intermittently. Am Med Assoc 1969; 207: infectious pathology except for the isolation of 923-8.

Table 3 Prospective studies with low-dose MTX treatment in our centre Number Patient population Study design Follow up time Folow up months Number ofMTX MTX-relatedpulmonary Reference perpatient treatedpatients pathology number ofcases 1 Refractory RA Open 1984-86 12 16 0 85 2 Follow up of number 1 Open 1986-92 72 12 0 86 3 RA Double-blind 1986-88 12 31 1 viral pneumonitis 87 MTX versus AZA 1 suspected viral pneumonitis 4 Follow up of number 3 Open 1988-92 48 25 2 MTX pneumonitis 71 5 RA Open 1991-92 6 40 0 88 MTX versus MTX + SASP 6 RA Double blind 1992 (ongoing) 12 90* 0 MTX versus SASP versus MTX + SASP 7 RA Open 1990-92 12 20 0 8 Early RA Open 1985 (ongoing) 67 0 89 9 Systemic sclerosis Open 1988-89 12 8 1 Pulmonary aspergillosis 29 10 Systemic sclerosis Double blind 1989-92 12 28 0 90 MTX versus Placebo 11 Ankylosing spondylitis Open 1992-93 9 13 0 *: ongoing study, 90 patients enrolled, treatment code has not been broken yet. AZA: azathioprine, SASP: sulphasalazine,69: 2 episodes of MTX pneumonitis presented in the same patient. 438 Barrera, Laaw, van Riel, Dekhuijzen, Boerbooenus, vani de Potte

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